Aorta-coronary and peripheral vein grafts arc known to have a high failure rate due to occlusive complications in the graft as a result of an accelerated atherosclerosis process that is designated as vein graft disease. A prominent factor promoting vein graft disease is endothelial cell damage as a result of over distention of the vein graft because of the high arterial pressure it becomes exposed to. The accelerated atherosclerosis process that eventually results in the occlusion of the graft is strongly enhanced in hypercholesterolemic patients.
Extravascular supports or stents have been shown to improve the outcome of graft procedures because they prevent overextension and can ameliorate the arterialisation process (balanced increase in smooth muscle cells located in the medial layer of the vessel wall of the vein graft) that is needed to adapt the vein graft to the arterial pressure. Studies have indicated that if properly supported by an extravascular stent (artificial tubing surrounding the graft vessel), vein graft thickening and atherosclerosis is strongly inhibited (Mehta et al. (1998) Nature Med. 4(2), 235). Thus far. stents have been used that have to be custom-adjusted during surgery, that interfere with X-ray graft imaging and remain in the patient long after the graft has adopted to its new environment and outgrown the need for support. The ideal extravascular support fits all grafts with minimal effort, is biodegradable, imaging compatible, porous and elastic (Hinrichs et al (1994) Biomaterials 15(2), 83). Fibrin polymers fit all these criteria (Stooker et al. (2002) Eur. J. Cardiothorac. Surg. 21(2), 212) and preliminary results show that following the treatment of vein grafts with a liquid fibrinogen/thrombin sealant, vessel wall thickening was decreased (Stooker et al. (2002) Eur. J. Cardiothorac. Surg. 21(2): 212).
Fibrinogen and thrombin are natural blood proteins that play a pivotal role in blood clotting. At the end of the cascade that causes blood to clot, thrombin triggers the conversion of soluble fibrinogen into an insoluble fibrin network. This network stops the bleeding and provides a matrix for cells involved in wound repair. Commercially available fibrin-based products that mimic this last step in the clotting cascade are currently used to treat topical bleeding and to promote tissue adhesion. Fibrin is a fully biodegradable matrix that supports the natural healing process and in addition to supporting in vivo haemostatic plug formation, is also involved in tissue repair and remodeling.
A disadvantage of these fibrin glues is that they consist of two separate solutions containing fibrinogen and thrombin respectively, which have to be mixed directly on the wound, to prevent a premature reaction of the components. These fibrinogen and thrombin components have to be stored separately as frozen liquids or as lyophilized powders that need to be reconstituted before use. Such glues are described in, for example, Stooker et al. (2002) Fur. J. Cardiothorac. Surg. 21(2): 212 and Stooker et al. (2003) Ann. Thor. Surg. 76:1533.
The fibrinogen glue is viscous and completely homogenously mixing with the non viscous thrombin solution is often not achieved before fibrin polymer formation starts. As a result, a non-homogenous fibrin polymer is formed which influences visco-elastic properties of the fibrin. These features make the controlled use (e.g. even vein graft coating) of fibrin glues for extravascular support difficult. Furthermore, the available fibrin glues use high ratios of thrombin/fibrinogen (5-20 1U thrombin/mg fibrinogen) which increases the risk of “free” active thrombin passing through the vessel wall into the blood stream (Dascombe et al. (1997) Thromb. Haemost. 78 (2), 947), where it may cause intravascular coagulation. Thrombin applied as a liquid—in particular when applied at high concentrations—poses therefore a safety risk.